NMDA receptor

Catalysis

Cannabinoid receptor

Rimonabant

Biotechnology

Biology

Ionotropic effect

Benzamide

Cannabinoid

Receptor

Thiazole

Biochemistry

Carboxamide

Stereochemistry

Cannabinoid receptor type 2

In vivo

G protein-coupled receptor

Structure–activity relationship

In vitro

Pharmacology

Antagonist

Medicine

Chemistry

Selectivity

Benzothiazole

Functional selectivity

European Journal of Medicinal Chemistry

The strong therapeutic potential of CB2 receptor agonists for use as anti-inflammatory agents that lack psychiatric side effects has attracted substantial interest. We herein describe the rational design and synthesis of novel thiazole and benzothiazole derivatives and the evaluation of their binding affinity and functional activity on CB1 and CB2 receptors. The series with the general formula N-(3-pentylbenzo [d]thiazol-2(3H)-ylidene) carboxamide (compounds 6a-6d) exhibited the highest affinity and selectivity towards CB2 receptors with Kis in the picomolar or low nanomolar range, and selectivity indices (Ki hCB1/Ki hCB2) reaching up to 429 fold. Notably, these compounds also demonstrated an agonistic functional activity in cellular assays with EC50s in the low nanomolar range. More interestingly, compound 6d, the 3-(trifluoromethyl)benzamide derivative, exhibited remarkable protection against DSS-induced acute colitis in mice model.

Structure-activity relationships of thiazole and benzothiazole derivatives as selective cannabinoid CB2 agonists with in vivo anti-inflammatory properties